Imidazobenzothiadiazepines

ABSTRACT

5-Diazacycloalkyl-imidazo[imidazo]2,1-b][1,3,5]benzothiadiazepines of the formula ##STR1## e.g. a compound of formula I wherein Ph=phenylene, m=2, n=3, R 1  and R 2  =H, and R 3  =methyl, oxides and salts thereof, are neuroleptic agents.

CROSS REFERENCE TO RELATED APPLICATION

This is a divisional application of application Ser. No. 259,261, nowU.S. Pat. No. 4,391,808, which is a continuation-in-part of applicationSer. No. 158,671 filed June 12, 1980, now abandoned.

SUMMARY OF THE INVENTION

The present invention concerns and has for its object the provision ofnew 5-diazacycloalkyl-imidazo [2,1-b][1,3,5]-benzothiadiazepines, moreparticularly of those corresponding to Formula I ##STR2## wherein eachof R₁ and R₂ is hydrogen, lower alkyl or lower alkanoyl, halogeno,cyano, carboxy, lower carbalkoxy, carbamoyl, sulfamoyl, mono- ordi-lower alkyl-(carbamoyl or sulfamoyl); Ph is 1,2-phenylene,unsubstituted or substituted by up to two members selected from loweralkyl, lower alkoxy, lower alkylthio, halogeno, trifluoromethyl,sulfamoyl, mono- or di-lower alkysulfamoyl; each of C_(m) H_(2m) andC_(n) H_(2n) is lower alkylene separating both nitrogen atoms by 2 or 3carbon atoms, and R₆ is hydrogen, lower alkyl, alkanoyl, alkoxycarbonyl,phenylalkoxycarbonyl, or hydroxyalkyl, wherein the hydroxy group isseparated from the nitrogen atom by at least 2 carbon atoms; their N-and/or S-oxides, lower alkylquaternaries and salts thereof, derived frompharmaceutically acceptable acids or bases; as well as of correspondingpharmaceutical compositions and of methods for the preparation andapplication of said products, which are useful neuroleptic agentslacking extrapyramidal side-effects, which are suitable, for example, inthe treatment or management of aggression, agitation and/or anxiety inmammals.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

A lower alkyl group R₁, R₂, R₃ and/or such present in a substituted1,2-phenylene Ph-group, as well as in said alkoxy, alkylthio or saidother alkylated groups, is above all methyl, but also ethyl, n- ori-(propyl, butyl, pentyl, hexyl or heptyl), e.g. 2-methylpropyl or3-methylbutyl; and alkanoyl is preferably acetyl or propionyl.

A halogen atom R₁ and/or R₂, or such present in Ph, is preferably fluoroor chloro, but also bromo.

A lower carbalkoxy, mono- or dialkylcarbamoyl or -sulfamoyl group R₁and/or R₂, or present in Ph, is preferably carbomethoxy, carbethoxy;mono- or dimethylcarbamoyl or -sulfamoyl respectively.

A 1,2-phenylene radical Ph is preferably unsubstituted, ormono-substituted in the benzene ring by said substituents, for examplemethyl or ethyl; methoxy, ethoxy or i-propoxy; methylthio or ethylthio;fluoro, chloro or bromo; trifluoromethyl; sulfamoyl, mono- ordimethylsulfamoyl.

A lower alkylene group C_(m) H_(2m) and C_(n) H_(2n) is especiallyethylene; but also 1,2- or 1,3-propylene, 1,2-, 1,3- or 2,3-butylene;thus forming with both adjacent nitrogen atoms preferably a piperazinoor homopiperazino moiety.

A lower alkoxycarbonyl or hydroxyalkyl group R₃ is preferablymethoxycarbonyl or ethoxycarbonyl; 2-hydroxy-(ethyl or propyl),3-hydroxy-(propyl or butyl) or 4-hydroxybutyl respectively.

Said N-oxides are preferably those in which R₃ is lower alkyl orhydroxyalkyl, and in which the oxygen is attached to the nitrogencarrying said R₃ group. Said S-oxides represent sulfoxides(SO) orsulfones (SO₂).

Similarly, said lower alkylquaternaries of the compounds of Formula Iare preferably derived from those wherein R₃ is lower alkyl orhydroxyalkyl, and wherein only the terminal piperazino orhomopiperazino-nitrogen atom is quaternized. The anions of saidquaternaries, as well as those of said acid addition salts, arepreferably those of pharmaceutically acceptable acids, e.g. those listedbelow. Those compounds of Formula I with R₁ and/or R₂ being carboxy,also form salts with such bases, e.g. ammonia, mono-, dl- or tri-loweralkylamines; lower alkyleneimines; morpholine, piperazine, pyridine orlower alkyl-derivatives of said cyclic bases; alkali metal or alkalineearth metal hydroxides.

The term "lower," referred to above or hereinafter in connection withorganic radicals or compounds respectively, defines such with up to 7,preferably up to 4, and advantageously those with one or two carbonatoms.

The compounds of the invention exhibit valuable pharmacologicalproperties, primarily neuroleptic activity. It is demonstrable in animaltests using advantageously mammals, e.g. mice, rats or monkeys, as testobjects. Said compounds can be administered to them enterally orparenterally, advantageously orally, or subcutaneously, intravenously orintraperitoneally, for example, within gelatin capsules, or in the formof starchy suspensions or aqueous solutions respectively. The applieddosage may range between about 0.01 and 100 mg/kg/day, preferablybetween about 0.05 and 10 mg/kg/day, advantageously between about 0.1and 5 mg/kg/day.

Said neuroleptic properties can be demonstrated in adult rats orsquirrel monkeys, which were trained to press a lever to avoid the onsetof an electric foot shock. Each lever press postpones the shock for 30seconds. Whenever the animal fails to press the lever once within saidperiod, brief (0.5 sec.) shocks are delivered at 15 second intervalsuntil the animal again presses the lever. Under control conditions theanimals press the lever at a moderately steady rate and seldom receivemore than five or six shocks during a 25-minute (rats) and up to 4-hourexperimental session. Said compounds, which are administered to theanimals 30, 90 and 210 minutes prior to the experimental session, blockthe learned conditioned avoidance behavior, manifested by a decrease inavoidance responding and a marked increase in shocks taken by theanimals. Both, the avoidance responses and failures (shocks received),are recorded separately for evaluation according to said SidmanAvoidance test. Compounds of the invention decrease avoidance responses,e.g. compound of example 1 decreases avoidance responses in rats andmonkeys at an oral dose of 10 mg/kg or lower.

The extrapyramidal side-effects (EPS) known from classical neuroleptics,have been found to induce a characteristic motor syndrome in squirrelmonkeys, which were previously exposed to repeated antipsychotictreatment. These movement disorders consist of dystonic postures anddyskinetic movements, and correlate much better with the reportedincidence of EPS in man, than does catalepsy or tremor in this monkey.Thus, the potential extrapyramidal liability, as well as the relativeincidence of other neurological signs, such as ptosis, can be assessedby observation of these adult male squirrel monkeys, weighing 700-1200g. They are treated with haloperidol (1.25 mg/kg) once weekly orbiweekly. After approximately 2-4 months of this treatment regimen,dystonic posture and dyskinetic movements are evident during 1-6 hoursafter administration of haloperidol. At no other time abnormal movementsare evident in these monkeys. After haloperidol-elicited dyskinesias haddeveloped, this regimen ends, and 1.25 mg/kg haloperidol is given onceevery 4-8 weeks as a control for comparison with test agents of thisinvention.

Said monkeys are individually observed at intervals of 2, 4 and 6 hoursafter treatment and the experiments are performed in an enclosedcubicle, which is equipped with a remotely controlled video observationsystem and a white noise generator. Observations are performed by twoindependent observers, neither of whom has prior knowledge of the agentadministered, nor the purpose of the experiment. A third person handlesthe monkeys during neurological examination. After initial observationsthrough the video system, the observers enter the cubicle, recording themonkeys' responses as "motor" (ambulation inside cage), "visual" (visualresponse but no ambulation) and "none" (no response). Activity, posture,tremors, salivation and other neurological signs are observed.Particular attention is devoted to the presence or absence of "bizarre",dystonic postures and dyskinetic movements, as previously characterized.The handler then removes the monkey from the cage and the monkey'sreactions are separately scored to the approach of the gloved hand, tothe initial touch during capture and to restraint after capture.Vocalization during capture is also recorded. The handler then evaluatesbody tone and pupil size, and scores the presence or absence of ptosis.Catalepsy is then assessed, if preliminary examination suggested thatthis sign might be present. The monkey is first positioned on the floorwith his head down, then at the entrance to the observation cage, andfinally inside the observation cage. If the monkey remains essentiallyimmobile in any of these positions for at least 5 seconds, catalepsy isjudged to be present. After the monkey re-enters, or is replaced insideits observation cage, it is again observed for at least 1 minute fordyskinesias. A given sign or rating, which differs from control, is onlyconsidered an agent-induced effect, if both observers recorded it duringany of the three observation periods. When one observer considered agiven sign to be of lesser magnitude than did the other observer, theless severe score is accepted. However, overall inter-observercorrespondence is good.

After administration of 10 mg/kg of the illustrative compound of Example1, only one of five monkeys showed any type of dyskinetic movement, andthat was confined to one form (writhing) only, as observed during one ofthree time periods. In contrast, severe dyskinesia, characterized byvarious types of dyskinetic movements, is recognized in all monkeystreated with haloperidol (1.25 mg/kg). Dyskinesias were also absentafter clozapine (10 mg/kg), but were apparent after a moderate dose ofhaloperidol (0.625 mg/kg) in five monkeys, and no dyskinesias wereobserved at any time after vehicle (excipient) treatment. However,clozapine produced hypersalivation in every monkey which was examined inthis experiment, but no hypersalivation was apparent after any othertreatment, including said Example 1 compound. Ptosis, catalepsy,reduction in body tone and reduced responses to the observers were notedin some or all monkeys after administration of said 3 illustrativeagents.

According to said, and other classical tests, the compounds of theinvention are useful neuroleptic (antipsychotic) agents, for example, inthe treatment or management of aggression, agitation or anxiety, and arevirtually devoid of extrapyramidal side-effects, as is clozapine in man.The absence of hypersalivation indicates advantages of said newcompounds over clozapine, however. They are also useful intermediates inthe preparation of other valuable products, especially ofpharmacologically active compositions.

Particularly useful for their neuroleptic properties are compounds ofFormula I, in which each of R₁ and R₂ is hydrogen, lower alkyl oralkanoyl, halogeno, cyano, carboxy, lower carbalkoxy, carbamoyl,sulfamoyl, mono- or di-lower alkyl-(carbamoyl or sulfamoyl); Ph is1,2-phenylene, (lower alkyl)-1,2-phenylene, (loweralkoxy)-1,2-phenylene, (lower alkylthio)-1,2-phenylene,(halogeno)-1,2-phenylene, (trifluoromethyl)-1,2-phenylene,(sulfamoyl)1,2-phenylene, (mono- or di-loweralkylsulfamoyl)-1,2-phenylene; each of m and n is the integer 2 or 3;and R₃ is hydrogen, lower alkyl, alkanoyl, alkoxycarbonylphenylalkoxycarbonyl, or hydroxyalkyl, wherein the hydroxy group isseparated from the nitrogen atom by at least 2 carbon atoms; their N-and/or S-oxides; lower alkylquaternaries; or a pharmaceuticallyacceptable acid addition salt thereof.

Outstanding compounds of the invention are those of Formula II ##STR3##wherein each of R₁ and R₂ is hydrogen or lower alkyl; R₄ is hydrogen,lower alkyl or lower 2- or 3-hydroxyalkyl; R₅ is hydrogen, lower alkyl,lower alkoxy, halogeno or trifluoromethyl; and p is an integer from 0 to2; the N-oxide thereof; or pharmaceutically acceptable acid additionsalts thereof.

Preferred are those compounds of Formula II, wherein each of R₁ and R₂is hydrogen or methyl; R₄ is alkyl or 2- or 3-hydroxyalkyl with up to 4carbon atoms; R₅ is hydrogen, methyl, methoxy, fluoro, chloro ortrifluoromethyl; and p is 0; the N-oxide thereof; or pharmaceuticallyacceptable acid addition salts thereof.

The compounds of the invention are prepared according to methods knownper se, advantageously by condensing compounds of Formulae III and IV##STR4## wherein X is halogeno, lower alkoxy, lower alkylthio, cyanatoor thiocyanato; Y is hydrogen or an alkali metal; and the remainingsymbols have the meaning given for Formula I and, if desired, convertingany resulting compound into another compound of Formula I.

Said condensation is advantageously carried our with an excess of thepiperazine IV (Y=H), or with equivalent amounts of said metalderivatives thereof, preferably when X is halogeno, lower alkylthio orthiocyanato, advantageously at temperatures between about 0° and 150°,and preferably in an appropriate solvent such as a lower alkanol, forexample amyl alcohol, dimethylformamide, hexamethylphosphoramide,toluene.

Another process for preparing the compounds of Formula I consists inring-closing the compounds of Formula V ##STR5## wherein Z is oxygen,sulfur, or NH, and the other symbols have the above-given meaning, underdehydrating, dehydrosulfurating conditions.

Said ring-closing conditions are achieved with strong dehydrating ordehydrosulfurating agents, such as phosphorous halides and/oroxyhalides, or cyanogen halides, with or without crown ether catalysts,such as 8-crown-6-ether, and with or without basic catalysts such astriethylamine or potassium carbonate, preferably in an inert solvent,such as dimethylformamide.

The novel starting imidazo[2,1-b][1,3,5]benzothiadiazepines of formulaIII are prepared according to ring closure methods known per se,advantageously by condensing compounds of formula VI wherein Ph, R₁ andR₂ have meaning given for compounds of formula III, ##STR6## withreactive carbonic acid derivatives such as phosgene, thiophosgene,1,1'-carbonyldiimidazole, cyanogen bromide or the like.

Compounds of formula III wherein X is hydroxy can in turn be convertedto compounds wherein X is sulfhydryl by conventional sulfurating agents,such as phosphorus pentasulfide, and these can be further derivatized tocompounds of formula wherein X is as defined above analogous to theprocedures illustrated by the examples herein.

The starting materials of Formula V can be obtained from that of the(tautomeric) precursors of Formula III, wherein X is hydroxy, thio oramino by condensing them with compounds of Formula IV in the presence orabsence of other bases, e.g. those listed above, preferably in an inertsolvent, such as methylene chloride or toluene at temperatures between0° and 150° advantageously between 10° and 50°. The ring openingreaction is preferably carried out at low temperature to minimize sidereactions when R₁ ' and R₂ ' represent reactive functional groups.

Alternately, starting materials of formula V, wherein R₃ is alkanoyl,alkoxycarbonyl or phenylalkoxycarbonyl, are prepared by condensing acompound of formula VI with a compound of formula VII wherein Y¹,represents halocarbonyl, halothiocarbonyl or cyano, and R₃ ' representsalkanoyl, alkoxycarbonyl or phenylalkoxycarbonyl, preferably in an inertsolvent, at temperatures between 0° and 150°.

The compounds of the invention so obtained can be converted into othercompounds of Formula I according to known methods. Thus, for example,those with R₃ being hydrogen or alkali metal, e.g., sodium or lithiumsalts thereof, can be reacted with substituted or unsubstitutedoxiranes, such as ethylene oxide, or reactive esters of unsubstituted orcorrespondingly substituted aliphatic or araliphatic alcohols such asmethanol, ethanol, allyl alcohol, propargyl alcohol, e.g. suchesterified by a strong inorganic or organic acid, above all hydrohalicacids, e.g. hydrochloric, hydrobromic or hydriodic acid; sulfuric or anaromatic sulfonic acid, e.g. p-toluene or m-bromobenzene sulfonic acid,in order to obtain the corresponding N-substituted compounds orquaternaries respectively, depending on the molar amount of thealkylating agent employed. Intermediates of formula I wherein R₃ isalkali metal are obtained by metallation with reactive organo metallicagents such as lithium diisopropylamide, with alkali metal alkoxidessuch as sodium methoxide, or alkali metal hydrides such as sodium orpotassium hydride.

Unsaturated compounds, such as those with R₃ being lower alkenyl, loweralkynyl may be hydrogenated with catalytically activated hydrogen toobtain compounds wherein R₃ is the corresponding lower alkyl.Conversely, resulting N-alkylated compounds can be converted intoN-unsubstituted compounds, e.g. by catalytic hydrogenolysis of N-benzylcompounds, or reaction of N-lower alkyl derivatives with lower alkylhaloformates, e.g. ethyl chloroformate, to yield N-acyl derivativeswhich, in turn, may be hydrolyzed to said unsubstituted compounds, thosewith R₃ =H, for example with aqueous bases, such as alkali metalhydroxides, such as aqueous sodium hydroxide solution.

Compounds of formula I wherein R₃ is hydroxyalkyl can also be preparedby first reacting corresponding compounds of Formula I, wherein R₃represents hydrogen, with reactive derivatives of corresponding glycols,glycolic acids or dicarboxylic acids, such as lower alkyl esters,halides or anhydrides thereof, or reactive esters of said glycols orglycolic acids derivatives, for example with hydrohalic or aromaticsulfonic acids, 1,2-dibromoethane or -propane, ethyl bromoacetate or-propionate, ethyl tosyloxyacetate; diethyl oxalate or malonate or ethyloxalyl chloride. The intermediates so obtained are either hydrolyzed orreduced with simple or complex light metal hydrides such as lithiumaluminum hydride, alone or with diborane to compounds of formula Iwherein R₃ is hydroxyalkyl.

Compounds of formula I wherein R₃ is methyl can be prepared by reactingthe corresponding compounds of formula I wherein R₃ represents hydrogenwith lower alkyl- or phenyl lower alkyl- haloformates, such as ethylchloroformate, to obtain compounds of formula I wherein R₃ isalkoxycarbonyl or phenylalkyloxy-carbonyl, and reducing said acylderivatives with simple or complex light metal hydrides such as lithiumaluminum hydride, sodium tri-t-butoxy or bis-(2-methoxyethoxy) aluminumhydride.

N-Acylated derivatives can be obtained from compounds of Formula I withR₃ being hydrogen, and corresponding reactive acid derivatives, e.g.,halides, simple or activated esters, such alkyl or cyanoalkyl esters,anhydrides or isocyanates. Resulting compounds of Formula I with R₁and/or R₂ being hydrogen, can be converted to the corresponding 3-and/or 4-(halo or acyl)-derivatives, e.g. by halogenation, preferablywith chlorine in acetic acid or under Friedel-Crafts-conditions, and/orby acylation with a trihaloacetyl halide or a halosulfonic acid,followed by treatment with an alkali metal lower alkoxide, hydroxide oramide. Resulting carboxylic or sulfonic acid derivatives may then behydrolyzed in known fashion, preferably under alkaline conditions and/oramidized with ammonia, mono- or di-lower alkylamines, and resultingcarboxyamides may be dehydrated to the corresponding nitriles accordingto conventional methods.

Resulting tertiary nitrogen compounds with R₃ different from hydrogen,can be converted into the N- and/or S-oxides, for example with hydrogenperoxide or organic peracids, such as lower peralkanoic or perbenzoicacids, e.g. peracetic or m-chloro-perbenzoic acid, advantageously attemperatures at or below room temperature with the latter, or up to 100°with diluted hydrogen peroxide in the presence of lower alkanoic acids,e.g. acetic acid. If only N-oxides are desired, care should be taken,especially with said peracids, in order to prevent S-oxidation at overlylong reaction times.

If only S-oxides are desired, compounds wherein R₃ is acyl, such asalkoxycarbonyl or phenylalkoxycarbonyl, are treated with hydrogenperoxide or organic peracids, preferably m-chloro-perbenzoic acidadvantageously at temperatures at or below room temperature to obtaineither sulfoxides (SO) or sulfones (SO₂) depending on the quantity ofperacid used. Resulting compounds with R₃ being phenylalkoxy carbonyl oralkoxycarbonyl so obtained can be converted to other compounds offormula I according to methods known per se and previously describedabove.

Finally, the compounds of the invention are either obtained in the freebasic form, or as a salt thereof. Any resulting base can be convertedinto a corresponding acid addition salt preferably with the use of atherapeutically useful acid or anion exchange preparation, or resultingsalts can be converted into the corresponding free bases, for example,with the use of a stronger base, such as a metal or ammonium hydroxideor a basic salt, e.g. an alkali metal hydroxide or carbonate, or acation exchange preparation. Said acid addition salts are such ofpharmaceutically acceptable inorganic or organic acids, such as strongmetalloidic acids, for example hydrohalic, e.g. hydrochloric orhydrobromic acid; sulfuric, phosphoric, nitric or perchloric acid; butpreferably such of aliphatic or aromatic carboxylic or sulfonic acids,e.g. formic, acetic, propionic, succinic, glycollic, lactic, malic,tartaric, gluconic, citric, ascorbic, maleic, fumaric, hydroxymaleic,pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic,4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotinic,methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic,toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamicacid. These or other salts, for example, the picrates, can also be usedfor purification of the bases obtained; the bases are converted intosalts, the salts are separated and the bases are liberated from thesalts. In view of the close relationship between the free compounds andthe compounds in the form of their salts, whenever a compound isreferred to in this context, a corresponding salt is also intended,provided such is possible or appropriate under the circumstances.

In case mixtures of geometrical or optical isomers of the abovecompounds, e.g. I to VII are obtained, these can be separated into thesingle isomers by methods in themselves known, e.g. by fractionaldistillation, crystallization and/or chromatography. Racemic productscan likewise be resolved into the antipodes, for example, by separationof diastereomeric salts thereof, e.g. by the fractional crystallizationof d- or l-tartrates.

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluents, preferably such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents respectively and/or inert atmospheres, at lowtemperatures, room temperature or elevated temperatures, preferably atthe boiling point of the solvents used, at atmospheric orsuperatmospheric pressure.

The invention further includes any variant of the present process, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or theprocess is discontinued at any stage thereof, or in which the startingmaterials are formed under the reaction conditions, or in which thereaction components are used in the form of their salts or opticallypure antipodes. Mainly those starting materials should be used in saidreactions, that lead to the formation of those compounds indicated aboveas being especially valuable, e.g. those of Formula II.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions comprising an effectiveamount thereof in conjunction or admixture with excipients suitable foreither enteral or parenteral application. Preferred are tablets andgelatin capsules comprising the active ingredient together with (a)diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, celluloseand/or glycine, (b) lubricants, e.g. silica, talcum, stearic acid, itsmagnesium or calcium salt and/or polyethyleneglycol, for tablets also(c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, if desired, (d) disintegrants, e.g. starches,agar, alginic acid or its sodium salt, enzymes of the binders oreffervescent mixtures and/or (e) absorbents, colorants, flavors andsweeteners. Injectable compositions are preferably aqueous isotonicsolutions or suspensions, and suppositories are advantageously preparedfrom fatty emulsions or suspensions. Said compositions may be sterilizedand/or contain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1 to 75%, preferably about 1 to 50%,of the active ingredient. A unit dosage for a mammal of about 50 to 70Kg weight may contain between about 5 and 100 mg of the activeingredient.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Centigrade, and all parts wherever given are parts by weight.If not mentioned otherwise, all evaporations are performed under reducedpressure, preferably between about 15 and 100 mmHg.

EXAMPLE 1

To the mixture of 501 g of 1-methylpiperazine and 6,000 ml of amylalcohol, 538 ml of 9.3N methanolic hydrogen chloride are added and themixture is stirred and distilled for 1 hour, during which time 1,000 mlof distillate is collected and the temperature reaches 131°. Thereuponanother 501 g of 1-methylpiperazine are added, followed by 618.5 g of5-methylthio-imidazo[2,1-b][1,3,5]benzothiadiazepine. The mixture isstirred under nitrogen at 132°-140° for 48 hours and evaporated at about80°-90°. The residue is dissolved in 3,000 ml of methylene chloride, thesolution washed 3 times with 1,000 ml of 3N aqueous sodium hydroxide and5 times with 1,000 ml of water. It is finally extracted 4 times with 750ml of 2N hydrochloric acid each, the combined extracts are washed oncewith 1,000 ml of methylene chloride, decolorized with 75 g of charcoal,filtered and the filtrate is basified with 500 ml of 29.9% aqueousammonia to a pH of 9-10. The mixture is extracted twice with 2,000 ml ofmethylene chloride, the combined extracts dried, filtered and evaporatedat about 60°. 2,810 g of this residue are dissolved in 14,000 ml of hotisopropanol, the solution treated with 563 g of charcoal, filtered andthe residue washed with 1,000 ml of cold isopropanol. The combinedfiltrates are reheated and again treated with 563 g of charcoal in thesame manner. The resulting clear solution is concentrated to 8,500 mland the concentrate allowed to stand in the refrigerator for 2 days. Thewhite precipitate is filtered off, washed 3 times with cold isopropanoland dried at 40°/5 mmHg, to yield the5-(4-methylpiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine of theformula ##STR7## melting at 145°-147°.

1,614 g thereof are dissolved in 5,450 ml of anhydrous ethanol at50°-60°, the solution filtered hot, the filter rinsed with 1,000 ml moreanhydrous ethanol and the combined filtrates are acidified with thesolution of 688 g of maleic acid in 1,600 ml of anhydrous ethanol whilestirring. The mixture is stirred while cooling to 25°, the precipitatecollected, washed twice with 800 ml of anhydrous ethanol and dried at75°/0.5 mm Hg, to yield the corresponding monomaleate melting at198°-199° with decomposition.

The starting material is prepared as follows: To 39,230 ml of 2Nhydrochloric acid, 7,500 g of aminoacetaldehyde dimethylacetal are addedduring 45 minutes while stirring under nitrogen, followed by 6,932 g ofpotassium thiocyanate, which are added all at once. The mixture isheated to 98°, stirred for 2 hours and allowed to cool to roomtemperature overnight. The resulting suspension is stirred and cooled to5°, filtered and the residue dried at 60°/5 mmHg, to yield theimidazole-2-thiol melting at 224°-226°.

2,468 g thereof are added to the solution of 1,604 g of 86.9% aqueouspotassium hydroxide in 24,700 ml of isopropanol while stirring undernitrogen at room temperature, followed by 4,986 g of2-bromo-nitrobenzene. The mixture is stirred and heated to 82°-85° for 5hours, cooled to 50° and diluted with 37,000 ml of water. The resultingsuspension is stirred at room temperature for 2 days, filtered, theresidue washed 6 times with 4,000 ml of water and 5 times with 3,700 mlof diethyl ether, and dried at 60°/5 mmHg, to yield the2-(o-nitrophenylthio)-imidazole melting at 178°-180°.

The mixture of 2,210 g thereof, 2,000 ml of water, 2,000 ml of ethanoland 1,700 g of iron powder is heated to 70° while stirring undernitrogen. After addition of 10 ml of concentrated hydrochloric acid themixture is refluxed for 1.5 hours, whereupon 200 ml of concentratedhydrochloric acid in 1,000 ml of ethanol are added during 95 minutes.The mixture is refluxed for 2 hours longer and 400 ml of 6N aqueoussodium hydroxide are added. The resulting suspension is diluted with2,000 ml of methanol, filtered and the residue is washed 3 times with1,000 ml of methanol. The combined filtrates are diluted with 40,000 mlof water, the resulting suspension allowed to settle overnight, theprecipitate is collected, washed twice with 2,000 ml of water and driedat 60°/5 mmHg, to yield the 2-(o-aminophenylthio)-imidazole melting at137°-138°.

4,775 g thereof are added to the mixture of 55,000 ml of methylenechloride and 6,975 ml of triethylamine, the mixture cooled to 3° and3,301 g of 85% thiophosgene in carbon tetrachloride are added during 2.5hours while stirring under nitrogen at 15°. Stirring is continued at 10°for 4 hours and at room temperature overnight. The resulting suspensionis filtered, the residue washed twice with 4,000 ml of methylenechloride and once with 20,000 ml of water and suspended in 11,000 ml of1.3N hydrochloric acid. The suspension is stirred for 2 hours, filtered,the residue washed 3 times with 4,000 ml of water and dried at 60°/5mmHg, to yield the imidazo[2,1-b][1,3,5]benzothiadiazepin-5(6H)-thionemelting at 156°-159°.

1,184 g thereof are added to the solution of 278 g of sodium methoxidein 22,500 ml of isopropanol and the mixture is stirred for 1.5 hoursunder nitrogen. Thereupon 791 g of methyl iodide are added during 30minutes and the mixture is stirred 3.5 hours longer at about 20°. It isdiluted with 45,000 ml of water and the resulting suspension stirred atroom temperature overnight. It is filtered, the residue washed 5 timeswith 4,000 ml of water and dried at 60°/5 mmHg, to yield the5-methylthio-imidazo[2,1-b][1,3,5]benzothiadiazepine melting at116°-118°.

Similarly the following starting materials are prepared from thecorrespondingly substituted 2-bromonitrobenzenes:

a. 8-methoxy-5-methylthio-imidazo[2,1-b][1,3,5]benzothiadiazepine,melting at 143°-146°;

b. 8-chloro-5-methylthio-imidazo[2,1-b][1,3,5]benzothiadiazepine meltingat 147°-149°;

c. 8-fluoro-5-methylthio-imidazo[2,1-b][1,3,5]benzothiadiazepine meltingat 174°-176°;

d. 8-methyl-5-methylthio-imidazo[2,1-b][1,3,5]benzothiadiazepine

EXAMPLE 2

To the solution of 480 mg of5-thiocyanatoimidazo[2,1-b][1,3,5]benzothiadiazepine in 1 ml ofhexamethylphosphoramide, 500 mg of 1-methylpiperazine are added during 5minutes while stirring under nitrogen at -5°. Stirring is continued for5 minutes at said temperature, and for 15 minutes at room temperature.The mixture is diluted with 80 ml of ethyl acetate, washed twice withsaturated aqueous sodium chloride, dried and evaporated. The residue isdissolved in 2 ml of acetone, the solution acidified with 300 mg ofmaleic acid and diluted with diethyl ether, to yield the5-(methylpiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepinemonomaleate, melting at 198°-199° with decomposition; it is identicalwith that of Example 1.

The starting material is prepared as follows: To the suspension of 1.44g of 50% sodium hydride in mineral oil and 150 ml of drytetrahydrofuran, 6.45 g ofimidazo[2,1-b][1,3,5]benzothiadiazepin-5(6H)-thione are added inportions, and the mixture is stirred at room temperature under nitrogenfor one hour. The resulting white suspension is cooled to 0° and thesolution of 3.5 g of cyanogen bromide in 10 ml of tetrahydrofuran areadded dropwise. The mixture is stirred at room temperature for 0.5 hourand evaporated. The residue is triturated with methylene chloride, themixture washed with water, dried, concentrated to a small volume, washedwith diethyl ether and filtered, to yield the5-thiocyanatoimidazo[2,1-b][1,3,5]benzothiadiazepine melting at111°-113°.

EXAMPLE 3

The mixture of 333 mg of1-[2-(imidazo-2-ylthio)-phenyliminothiocarbonyl]-4-methylpiperazine, 3.3ml of dimethylformamide, 276 mg of potassium carbonate, 116 mg ofcyanogen bromide and 50 mg of 8-crown-6 ether is stirred at roomtemperature under nitrogen for 3 hours. It is diluted with ethylacetate, washed with saturated aqueous sodium chloride, dried andevaporated. The residue is dissolved in acetone, the solution treatedwith 116 mg of maleic acid and diluted with diethyl ether, to yield the5-(4-methylpiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepinemonomaleate, melting at 198°-199° with decomposition; it is identicalwith that of Example 1.

The starting material is prepared as follows: The mixture of 2.3 g ofimidazo[2,1-b][1,3,5]benzothiadiazepin-5(6H)-thione, 23 ml of methylenechloride and 1.0 g of 1-methylpiperazine is stirred at room temperaturefor 15 hours. The crystalline product formed is filtered off and washedwith methylene chloride, to yield the1-[2-(imidazo-2-ylthio)-phenyliminothiocarbonyl]-4-methylpiperazinemelting at 209°-212°.

EXAMPLE 4

To the suspension of 3.1 g of1-[2-(imidazo-2-ylthio)-phenyliminocarbonyl]-4-methylpiperazine and 25ml of phosphorus oxychloride, 2.04 g of phosphorus pentachloride areadded at once, and the mixture is stirred at room temperature for 4hours. It is evaporated, the residue suspended in 50 ml of dry methylenechloride, the suspension cooled to 0° and 2.02 g of triethylamine areadded dropwise while stirring. Stirring is continued for 15 minutes at0°, the mixture washed with water, dried and evaporated. The residue isdissolved in acetone and the solution acidified with maleic acid, toyield the 5-(4-methylpiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepinemonomaleate, melting at 198°-199° with decomposition; it is identicalwith that of Example 1.

The starting material is prepared as follows: The mixture of 15 g of2-(imidazo-2-ylthio)-aniline, 13.9 g of 1,1'-carbonyldiimidazole and 675ml of methylene chloride is stirred at room temperature for 24 hours.The solids formed are filtered off and washed with methylene chloride toyield the imidazo[2,1-b][1,3,5] benzothiadiazepin-5-(6H)-one, melting at250°-252° with decomposition.

In the analogous manner (or by replacing the 1,1'-carbonyldiimidazole bythe equivalent amount of phosgene), the following intermediates areobtained and are illustrative of the process:

a. 3,4-dimethylimidazo[2,1-b][1,3,5]benzothiadiazepin-5(6H)-one, m.p.225° (dec.);

b. 8-chloroimidazo[2,1-b][1,3,5]benzothiadiazepin-5(6H)-one, m.p.261°-263°;

c. 8-trifluoromethylimidazo[2,1-b][1,3,5]benzothiadiazepin-5(6H)-one,m.p. 257°-260°.

d. 3-methylimidazo[2,1-b][1,3,5]benzothiadiazepin-5(6H)-one, m.p.225°-229°.

The mixture is 2.17 g of imidazo[2,1-b][1,3,5]benzothiadizepin-5(6H) 1.0g of 1-methyl piperazine and 20 ml of methylene chloride is stirred atroom temperature for 24 hours. The crystalline product formed isfiltered off and washed with methylene chloride, to yield the1-[2-(imidazo-2-ylthio)-phenyliminocarbonyl]-4-methylpiperazine, meltingat 197°-200°.

In similar manner the following additional starting materials areobtained and are illustrative of the process:

a.1-[2-(4-methylimidazo-2-ylthio)-phenyliminocarbonyl]-4-methylpiperazinemelting at 101°-5° (dec.).

b. 1-[2-(imidazo-2-ylthio)-phenyliminocarbonyl]-4-methylhomopiperazine,melting at 134°-138°.

c. 1-[2-(imidazo-2-ylthio)-phenyliminocarbonyl]-4-carboethoxypiperazine,melting at 161°-170°.

d.1-[2-(imidazo-2-ylthio)-phenyliminocarbonyl]-4-carbobenzoxypiperazine,melting at 206°-208°.

e. 1-[2-(4-carboethoxyimidazo-2-ylthio)-phenyliminocarbonyl]-4-methylpiperazine, melting at 166°-169°.

f. 1-[2-(imidazo-2-ylthio)-4-trifluoromethylphenyliminocarbonyl]-4-methylpiperazine melting at 212°-214° C.

EXAMPLE 5

A mixture of 10 g of5-methylthio-imidazo[2,1-b][1,3,5]benzothiadiazepine hydrochloride, 3.62g of piperazine, and 350 ml of amyl alcohol is refluxed with stirringand under nitrogen for 20 hrs. The solvent is evaporated under vacuum,the residue is triturated with methylene chloride, washed with 2N sodiumhydroxide solution, dried over MgSO₄, and evaporated to dryness. Theresidue is dissolved in 10 ml of methanol and treated with 2N etherealhydrochloric acid solution to give5-(4H-piperazino)imidazo[2,1-b][1,3,5]benzothiadiazepinedihydrochloride, melting at 249° C. with decomposition.

EXAMPLE 6

A mixture of 5 g of 5-methylthio-imidazo[2,1-b][1,3,5]benzothiadiazepinehydrochloride, 2.86 g of N-β-hydroxyethylpiperazine, and 175 ml of amylalcohol is refluxed under nitrogen for 48 hrs. with stirring. Thesolvent is removed under vacuum, the residue is triturated withmethylene chloride, washed with 2N sodium hydroxide solution, dried overMgSO₄, and evaporated to dryness. The residue is dissolved in 5 ml ofmethanol and treated with 2N ethereal hydrochloric acid solutions togive 5-(4-β-hydroxyethylpiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine dihydrochloride melting at 212°-214°.

EXAMPLE 7

By replacement of the N-β-hydroxyethylpiperazine in example 6 by anequivalent amount of N-methylhomopiperazine one obtains5-(4-methylhomopiperazino)imidazo[2,1-b][1,3,5]benzothiadiazepine,isolated as the fumarate salt melting at 216°-8°.

EXAMPLE 8

According to the methods illustrated by the previous examples, thefollowing compounds of Formula I are obtained from equivalent amounts ofthe corresponding starting materials; Ph═4-R₅ -1,2-phenylene; C_(m)H_(2m) ═(CH₂)₂ ; C_(n) H_(2n) ═(CH₂)_(n').

    __________________________________________________________________________    No.                                                                              R.sub.1                                                                            R.sub.2                                                                          R.sub.3 n'                                                                              R.sub.5                                                                           Salt m.p. °C.                                 __________________________________________________________________________    1  H    H  H       2 H   2HCl 249 dec.                                        2  H    H  CH.sub.3                                                                              2 H   2HCl 216-219                                         3  H    H  CH.sub.3                                                                              2 OCH.sub.3                                                                         2HCl 155 dec.                                        4  H    H  CH.sub.3                                                                              2 F   maleate                                                                            202-204                                         5  H    H  CH.sub.3                                                                              2 Cl  2HCl 203-206                                         6  H    H  CH.sub.3                                                                              2 CF.sub.3                                                                          2HCl 180 dec.                                        7  CO.sub.2 C.sub.2 H.sub.5                                                           H  CH.sub.3                                                                              2 H   --   138-141                                         8  H    H  (CH.sub.2).sub.2 OH                                                                   2 H   2HCl 210-212                                         9  H    H  COOEt   2 H   --   137-139                                         10 H    H  CH.sub.3                                                                              3 H   fumarate                                                                           216-218                                         11 H    H  COOCH.sub.2 C.sub.6 H.sub.5                                                           2 H   --   NMR: 5.2, 3.5                                   12 CH.sub.3                                                                           H  CH.sub.3                                                                              2 H   maleate                                                                            191-192.5                                       13 CH.sub.3                                                                           CH.sub.3                                                                         CH.sub.3                                                                              2 H                                                        __________________________________________________________________________

EXAMPLE 9

To the solution of 0.2 g of5-(4-carboethoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine in 2ml of dry tetrahydrofuran, 100 mg of lithium aluminum hydride are addedat once and the mixture is refluxed under nitrogen for 48 hrs. Themixture is cooled to room temperature, stirred with 0.2 ml of 30% sodiumhydroxide, and filtered. The filtrates were evaporated to dryness andthe product is purified to give5-(4-methylpiperazino]-imidazo[2,1-b][1,3,5]benzothiadiazepine, meltingat 145°-7°, and identical to compound obtained in example 1.

EXAMPLE 10

To the solution of 88 mg of5-(4-methylpiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine in 1 mlof methylene chloride, 74 mg of m-chloroperbenzoic acid are added at 0°C. The mixture is stirred at 0° C. overnight; this is diluted with 1 mlof ether, one equivalent of ethereal hydrochloric acid solution is addedand the resulting precipitate is collected. Recrystallization frommethanol-ethyl acetate yields5-(4-methyl-4-oxidopiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepinehydrochloride, melting at 155° with decomposition.

EXAMPLE 11

(a) To the solution of 0.5 g of5-(4-carbobenzoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine in5 ml of methylene chloride, cooled at 0° C., is added dropwise asolution of 0.26 g of m-chloroperbenzoic acid dissolved in 2 ml ofmethylene chloride. The mixture is stirred at 0° C. for 1.5 hrs., thesolids are filtered, and the filtrates are washed with 10% aqueouspotassium carbonate and water, then dried over magnesium sulfate andevaporated to dryness to give5-(4-carbobenzoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine1-oxide.

Mass spec.: m/e 435, 418, 387.

(b) In a similar manner and by using 0.61 g (2 equivalents) ofm-chloroperbenzoic acid, the5-(4-carbobenzoxypiperazino]-imidazo[2,1-b][1,3,5]benzothiadiazepine1,1-dioxide is obtained.

Mass spec.: m/e 451, 420, 406, 386.

EXAMPLE 12

(a) To the solution of 100 mg of5-(4-carbobenzoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine1-oxide in 0.3 ml of acetic acid are added 0.35 ml of a 2N solution ofhydrobromic acid in acetic acid. The mixture is heated at 100° C. for 1hr. and stirred at room temperature overnight. Ether is added, and the5-(4H-piperazino)-imidazo[2,1-b][1,3,5,]benzothiadiazepine 1-oxidehydrobromide is filtered and washed with ether; m.p. 75° dec.

(b) In a similar manner the5-(4-carbobenzoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine1,1-dioxide is converted to5-(piperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine 1,1-dioxidehydrobromide. Rf=0.353 (silica gel, ethyl acetate-methylene chloride,1:1).

EXAMPLE 13

A mixture of 285 mg of5-(4H-piperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine, 0.5 g ofpotassium carbonate, 0.142 g of methyl iodide and 2 ml of acetone isstirred at room temperature overnight and evaporated. Water is added tothe residue, and the mixture is extracted with methylene chloride. Theextracts are dried over magnesium sulfate, evaporated, and the residueis purified to give5-(4-methylpiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine meltingat 145°-7° and identical to compound obtained in Example 1.

EXAMPLE 14

Preparation of 10,000 tablets each containing 5 mg of the activeingredient:

    ______________________________________                                        Formula:                                                                      ______________________________________                                        5-(4-methylpiperazino)-imidazo[2,1-b]                                                                 50.00    g                                            [1,3,5]benzothiadiazepine maleate                                             Lactose                 1,157.00 g                                            Corn starch             75.00    g                                            Polyethylene glycol 6,000                                                                             75.00    g                                            Talcum powder           75.00    g                                            Magnesium stearate      18.00    g                                            Purified water          q.s.                                                  ______________________________________                                    

Procedure:

All the powders are passed through a screen with openings of 0.6 mm.Then the drug substance, lactose, talcum, magnesium stearate and half ofthe starch are mixed in a suitable mixer. The other half of the starchis suspended in 40 ml of water and the suspension added to the boilingsolution of the polyethylene glycol in 150 ml of water. The paste formedis added to the powders which are granulated, if necessary, with anadditional amount of water. The granulate is dried overnight at 35°,broken on a screen with 1.2 mm openings and compressed into tabletsusing concave punches with 6.4 mm diameter, uppers bisected.

EXAMPLE 15

Preparation of 10,000 capsules each containing 10 mg of the activeingredient:

    ______________________________________                                        Formula:                                                                      ______________________________________                                        5-[4-(2-hydroxyethyl)-piperazino]-                                                                    100.0   g                                             imidazo[2,1-b][1,3,5]benzothia-                                               diazepine dihydrochloride                                                     Lactose                 1,800.0 g                                             Talcum powder           100.0   g                                             ______________________________________                                    

Procedure:

All the powders are passed through a screen with openings of 0.6 mm.Then the drug substance is placed in a suitable mixer and mixed firstwith the talcum, then with the lactose until homogenous. No. 3 capsulesare filled with 200 mg, using a capsule filling machine.

Analogously tablets or capsules are prepared from the remainingcompounds of the invention, e.g. those illustrated by the other examplesherein.

What is claimed is:
 1. A 5-diazacycloalkyl-imidazo[2,1-b][1,3,5]benzothiadiazepine compound of the formula ##STR8## wherein each of R₁ and R₂ is hydrogen or lower alkyl; Ph is 1,2-phenylene, unsubstituted or substituted by one member selected from lower alkyl, lower alkoxy, lower alkylthio, halogeno, trifluoromethyl, sulfamoyl, mono- or di-lower alkylsulfamoyl; C_(m) H_(2m) is lower alkylene separating both nitrogen atoms by 2 carbon atoms; C_(n) H_(2n) is lower alkylene separating both nitrogen atoms by 3 carbon atoms; and R₃ is lower alkyl or lower hydroxyalkyl wherein the hydroxy group is separated from the nitrogen atom by 2 carbon atoms; the oxides thereof; or a pharmaceutically acceptable salt thereof.
 2. A compound as claimed in claim 1, in which formula each of R₁ and R₂ is hydrogen or lower alkyl; Ph is 1,2-phenylene, (lower alkyl)-1,2-phenylene, (lower alkoxy)-1,2-phenylene, (lower alkylthio)-1,2-phenylene, (halogeno)-1,2-phenylene, (trifluoromethyl)-1,2-phenylene, (sulfamoyl)-1,2-phenylene, (mono- or di-lower alkylsulfamoyl)-1,2-phenylene; m is the integer 2; n is the integer 3; and R₃ is lower alkyl or lower hydroxyalkyl wherein the hydroxy group is separated from the nitrogen atom by 2 carbon atoms; the oxides thereof; or a pharmaceutically acceptable acid addition salt thereof.
 3. A compound as claimed in claim 2 being 5-(4-methylhomopiperazino)imidazo[2,1-b][1,3,5]benzothiadiazepine or a pharmaceutically acceptable salt thereof. 